To study the physiological effect of the overexpression of myocardial Gs` (protein levels increased by approximately 3-fold) in transgenic mice, we examined the responsiveness to sympathomimetic amines by echocardiography (9 MHz) in 5 transgenic mice and 5 control mice (both 10.3q0.2 months old). Myocardial contractility in transgenic mice, as assessed by LV fractional shortening (FS) and ejection fraction (EF) was not different from that of control mice at baseline (LVFS 40q3 vs 36q2%, EF 78q3 vs 74q3). LVFS and EF in transgenic mice during isoproterenol (ISO) 0.02fg/kg/min infusion were higher than those in control mice (LVFS 68q4 vs 48q3%, EF 96q1 vs 86q3%, p<0.05). Norepinephrine (NE) 0.2fg/kg/min infusion also increased LVFS and EF in transgenic mice more than those in control mice (LVFS 59q4 vs 47q3%, EF 93q2 vs 85q3%, p<0.05). Heart rates of transgenic mice were higher than those of control mice during ISO and NE infusion. In three transgenic mice with heart rate held constant, LV dP/dt rose by 33q2% with ISO, 0.02 g/kg/min and by only 13q2% in three wild type controls (p<0.01). NE, 0.1 g/kg/min, also induced a greater effect on LV dP/dt in the three transgenic mice with heart rate constant, as compared with three wild type controls (65q8% vs 28q4%, p<0.05). Pathological and histological analyses of older transgenic mouse hearts (16.0q0.8 months old) revealed hypertrophy, degeneration, atrophy of cells and replacement fibrosis reflected by significant increases in collagen volume in the subendocardium (5.2q1.4% vs 1.2q0.3%, p<0.05) and in the cross sectional area of myocytes (298q29fm2 vs 187q12fm2,, p<0.05) as compared to controls. These results suggest that Gs` overexpression enhanced the efficacy of the -adrenergic receptor-Gs-adenylyl cyclase signaling pathway. This in turn leads to augmented inotropic and chronotropic responses to endogenous sympathetic stimulation. This action over the life of the animal results in myocardial damage characterized by cellular degeneration, necrosis and replacement fibrosis, with the remaining cells undergoing compensatory hypertrophy. As a model, this transgenic mouse offers new insight into mechanisms of cardiomyopathy and heart failure and provides a new tool for their study.